2. Academic Validation
  3. Tipranavir analogs as antiviral agents: Design, synthesis, in vitro, and in silico study of new SARS-CoV-2 main protease inhibitors

Tipranavir analogs as antiviral agents: Design, synthesis, in vitro, and in silico study of new SARS-CoV-2 main protease inhibitors

  • Bioorg Chem. 2025 May 23:163:108624. doi: 10.1016/j.bioorg.2025.108624.
Selwan M El-Sayed 1,  Dina I A Othman 2,  Ghada S Hassan 3,  Ahmed H E Hassan 3,  Shahenda M El-Messery 4,  Ahmed R El-Sheakh 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura National University, Gamasa, 7731168, Egypt. Electronic address: salwanmahmoud@mans.edu.eg.
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 3 Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 4 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: habib2001@mans.edu.eg.
  • 5 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, 7731168, Egypt; Future studies and Risks management' National Committee of Drugs, Academy of Scientific Research, Ministry of Higher Education, Elsayeda Zeinab, Egypt.
PMID: 40441028 DOI: 10.1016/j.bioorg.2025.108624
Abstract

The current study aims at developing non-peptidic new Antiviral hits against main protease (Mpro) of SARS-COV2 using the non-peptidic Mpro inhibitor tipranavir (TPV) as a starting point. In vitro protease inhibition assay of the targeted compounds indicated that compound 6f and its cyclized triazole analogue 7f were the most active in the present study with IC50 values of 6.48 and 7.38 μM, respectively. These values were better than the 9.06 μM IC50 value of reference standard; TPV. In general, acylthiosemicarbazide derivatives 6e-g were more potent than corresponding acylsemicarbazide derivatives 6a-c. Also, the 4-chlorophenyl combined with either thiosemicabazide or 5-mercaptotriazolyl moieties in the molecules were the best for protease inhibitory activity. Cytotoxicity testing assay suggested that the tested molecules were relatively safe for the normal human lung fibroblast cell line WI-38 with IC50 values that ranged from 48.75 to 399.96 μM. Results of the molecular modeling study were consistent with those of in vitro biological evaluation. Collectively, compounds 6f and 7f could be considered as non-peptidic new Antiviral hits with protease inhibitory activity for further modifications and development to potent Antiviral agents as Protease Inhibitors.

Keywords

Coronaviruses; Main protease inhibitors; Sulfonamides; Triazoles.

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